Metabolic abnormalities in diabetic peripheral nerve are thought to heavily influence the development of diabetic neuropathy, probably the most common and one of the most disabling unsolved complications of diabetes. Recent studies from this laboratory have suggested that hyperglycemia initiates a cyclic metabolic defect in diabetic peripheral nerve involving competitive inhibition of Na-dependent myo-inositol (MI) uptake by glucose, reduced nerve MI content, impaired MI-phospholipid metabolism, and secondary impairment of the membrane-bound phospholipid-dependent enzyme Na/K-ATPase, which further impairs Na-dependent MI uptake. This newly-recognized self-reinforcing metabolic defect, which is prevented by the administration of insulin, MI, or the aldose reductase inhibitor sorbinil, is felt to contribute to nerve dysfunction in experimental diabetes. The planned research addresses two unanswered questions which are central to the proposed scheme: How does the aldose reductase inhibitor sorbinil prevent or reverse the proposed self-reinforcing metabolic defect? How does nerve MI depletion impair the function of nerve Na/K-ATPase? The direct and indirect effects of sorbinil on the MI-Na/K-ATPase cycle will be assessed. Two hypotheses will be tested concerning the relationship of MI metabolism to Na/K-ATPase function: one postulates a tightly-bound phosphoinositide fraction intimately associated with the membrane-bound Na/K-ATPase which regulates its function; the second invokes a phospholipid-dependent protein kinase C phosphorylation of either the Na/K-ATPase or a closely associated membrane protein. These questions will be approached using in vitro peripheral nerve preparations developed in this laboratory, and using isolated Na/K-ATPase-enriched membrane fractions isolated from peripheral nerve of animals with experimental diabetes.